The dendritic cell (DC) system, comprising the myeloid (MDC) and plasmacytoid (PDC) subsets, orchestrates innate and adaptive immunity to pathogens. DCs are located within the epithelial tissues (Langerharis cells, LCs) and in the underlying lymphoid follicles (PDCs and MDCs) that line the oral cavity. Therefore, DCs are in prime positions to encounter oral pathogens and may play an important role in sustaining a healthy oral mucosa. Increasing evidence highlights how DCs both produce and respond to innate factors such as type I IFNs and defensins that possibly provide important barriers against HIV infection as well as in controlling commensal organisms in the oral cavity. We hypothesize that unlike HIV, organisms like herpes simplex virus (HSV) or Candida albicans will trigger strong innate type I IFN and defensin responses in DCs that contribute to the resistance of the oral mucosa to HIV infection as well as controlling HSV and Candida infections in healthy people. However, prior exposure to HIV will impede these innate DC responses rendering individuals more susceptible to HSV infection and reactivation as well as candidiasis. Three major questions will be addressed to investigate this. 1. Are defensin responses in LCs induced by HIV and organisms present in the oral cavity? 2. What are the innate type I IFN and defensin responses of PDCs and MDCs to HIV and oral pathogens? 3. Do epithelial cells and keratinocytes influence the innate responses of DCs to HIV and oral pathogens? By investigating these issues we will reveal the innate responses of distinct DC subsets that are found in the tissues of the oral cavity to HIV and related co-pathogens, how these responses are influenced by cell-cell (DCs, epithelial cells, and keratinocytes) contact, and whether prior exposure to one organism alters a DCs' response to another. The involvement of specific receptors (toll like receptors, TLRs and C-type lectin receptors, CLRs) will be examined to elucidate their role in capture of a pathogen vs signaling of cellular responses. These extensive in vitro studies will uncover pertinent information about the innate responses of DCs to various infections and how these contribute to a healthy oral environment that is perturbed in HIV infected individuals. This will afford critical insight as to how such responses could be boosted to prevent opportunistic infections and also identify potential targets for the development of strategies to prevent HIV transmission across the oral and other mucosal surfaces.